JP 2002-513763 T (Patent Literature 1), JP 2002-154397 A (Patent Literature 2), JP 2002-521489 T (Patent Literature 3) disclose CpG oligonucleotide and the method of manufacturing them.
JP 2010-504750 T (Patent Literature 4) discloses that oligonucleotides, which have lipophilic substituted nucleotide analogues out of CpG motif, cause production of interferon-α (IFN-α).
Following Non Patent Literature 1 discloses that the S-form stereoisomer of CpG oligonucleotide trimer promotes MAPK signal.
Following Non Patent Literature 2 discloses PF-3512676 (Sequence No. 119), all parts of the sequence are phosphorothioated and S-form stereoisomer. Natural oligonucleic acid is readily reduced in vivo. Whereas, that are changed phosphodiester of oligo nucleic acid (P—O bond) to phosphoric acid thioester bond (P—S bond), P—S modifications are difficult to be reduced in vivo.
The following Non-Patent Literature 3 discloses that the CpG oligonucleotide (oligonucleotide having a CpG sequence) activates Th1 immune path through the Toll-like receptor (TLR9). CpG oligonucleotides can be classified into three types: class A-C. In CpG oligonucleotides classified as class A, the 3′ and 5′-phosphate-binding site of the end of 1-4 bases are phosphorothioate linkages (PS-binding), shows a strong IFN-α production inducing ability. However, its effects on B cell proliferation is weak. On the other hand, CpG oligonucleotides are classified as class B and C, all the phosphate binding sites are of S, shows a strong B-cell proliferation effect. However, its IFN-α production inducing ability is not so strong. Natural oligonucleic acid consist of phosphodiester bonds (PO bond) is readily reduced in vivo.
The following non-patent literature 4 discloses the anti-tumor activity of A-class and B-class CpG oligonucleotide.
Both Class CpG oligonucleotide showed anti-tumor activity when they were administered in combination with cancer antigens. However, there was no effect when administered oligonucleotides alone. In order to express the activity, they should be administered as liposome formulations to prevent degradation in vivo.
The following patent literature 5 discloses a pharmaceutical composition for the tumor treatment including an adjuvant. The following patent literature 6 discloses a anti-tumor agent which comprises an adjuvant consist of a CpG oligonucleotide and comprises an oligonucleotide as an effective ingredient.